rs368913905

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.1610C>T(p.Thr537Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,585,728 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T537T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 8 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 2.02

Publications

3 publications found

Variant links:

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

NPHS1 Gene-Disease associations (from GenCC):

congenital nephrotic syndrome, Finnish type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04666382).

BP6

Variant 19-35846025-G-A is Benign according to our data. Variant chr19-35846025-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180462.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004646.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.1610C>T	p.Thr537Met	missense	Exon 12 of 29	NP_004637.1	O60500-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.1610C>T	p.Thr537Met	missense	Exon 12 of 29	ENSP00000368190.4	O60500-1
NPHS1	ENST00000869106.1		c.1550C>T	p.Thr517Met	missense	Exon 12 of 29	ENSP00000539165.1
NPHS1	ENST00000353632.6	TSL:5	c.1610C>T	p.Thr537Met	missense	Exon 12 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00104

AC:

213

AN:

204354

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000468

Gnomad ASJ exome

AF:

0.000983

Gnomad EAS exome

AF:

0.0000644

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000381

GnomAD4 exome

AF:

0.000654

AC:

937

AN:

1433514

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

612

AN XY:

710454

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32860

American (AMR)

AF:

0.000444

AC:

AN:

40556

Ashkenazi Jewish (ASJ)

AF:

0.000939

AC:

AN:

25568

East Asian (EAS)

AF:

0.0000523

AC:

AN:

38220

South Asian (SAS)

AF:

0.00711

AC:

585

AN:

82246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50844

Middle Eastern (MID)

AF:

0.00366

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000221

AC:

243

AN:

1098162

Other (OTH)

AF:

0.000725

AC:

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000427

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41548

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00539

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

67998

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000397

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000936

AC:

113

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Finnish congenital nephrotic syndrome (3)

Congenital nephrotic syndrome (1)

Focal segmental glomerulosclerosis (1)

not provided (1)

NPHS1-related disorder (1)

Proteinuria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0063

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.047

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.6

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.74

MVP

0.91

MPC

0.70

ClinPred

0.087

GERP RS

3.7

Varity_R

0.16

gMVP

0.75

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over